The main emphasis in this project has recently been on the role of transforming growth factor alpha (TGF-alpha) in the growth and differentiation of the hepatic stem cell compartment. The expression of (TGF-alpha) was studied in hepatocytes following partial hepatectomy and also during hepatic differentiation in fetal, neonatal hepatocytes and in adult liver after acetylaminofluorene (AAF) administration by using both Northern blot and in situ hybridization methods. The level of TGF-alpha expression was increased six- to eightfold after partial hepatectomy and was also observed in the fetal and neonatal hepatocytes. Proliferating oval cells, perisinusoidal stellate cells, as well as basophilic foci generated by the modification of the Solt-Farber protocol, were positive for TGF-alpha transcripts. The observation that TGF-alpha is expressed in both fetal and differentiating hepatic cells suggests that one of the TGF-alpha effects, in addition to the mitogenic stimulation, may involve the induction of hepatocytic differentiation in primitive liver cells. In contrast, heparin binding growth factor (HBGF-1) showed only a slight increase during fetal development but was observed to be significant in the liver treated with AAF.